Cancer Treat Rev: Therapeutic strategies for diffuse large B-cell lymphoma

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype

To further improve outcomes in patients with DLBCL in first-line therapy, a number of academics have worked over the past decade and used new therapies

Efficacy was improved compared to R-CHOP in first-line therapy

Table 1 summarizes several strategies

Increases the intensity of treatment

One of the attempts to improve first-line treatment is to use a more robust chemotherapy regimen

In the LNH03-2B study ([2] in Table 1), 380 patients aged 18-59 years with untreated DLBCL and aa-IPI score equal to 1 were randomized to receive intensive treatment with standard R-CHOP or R-ACVBP (rituximab, doxorubicin, cyclophosphamide, vindesin, bleomycin, and prednisone) and repeated every 2 weeks

The role of high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) as first-line consolidation therapy has been explored in three studies

Two other randomized studies have also explored the role of HDC combined ASCT relative to R-CHOP or R-CHOEP as first-line consolidation therapy with similar

The Alliance/CALGB 50303 study ([7] in Table 1) compared 6-cycle DA-EPOCH-R (dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab) with standard R-CHOP as the first-line treatment

Alternative CD20 monoclonal antibody

Large, randomized Phase III GOYA studies ([9] in Table 1) evaluated the efficacy of second-generation anti-CD20 monoclonal otolizumab in DLBCL

R-CHOP+X

Another different and attractive strategy is to add novel biological drugs ('X') to standard R-CHOP, either during the induction phase or as a maintenance phase (Figure 1

Lenalidomide has shown activity in R/R DLBCL and has been shown to benefit in first-line therapy in combination with R-CHOP (i.

Similarly, bortezomib plus R-CHOP (VR-CHOP) also failed to improve outcomes in phase II PYRAMID studies and Phase III REMoDL-B phase III studies ([12,13] in Table 1); The latter study also stratified patients according to cell of origin (COO) classification with consistent outcomes

Ibutinib has shown a noteworthy activity in R/R ABC DLBCL, possibly related

Recently, polarix studies ([15] in Table 1) explored an improved protocol in which vincristine was replaced by Poratuzumab vedotin (pola-R-CHP); Vincristine

The Phase II CAVALLI study ([16] in Table 1) evaluated the addition of the selective BCL-2 inhibitor Venequera to R-CHOP, particularly in poor prognosis populations

Finally, there are a number of drugs that have been studied as maintenance therapy after standard R-CHOP induction, but the results have been unsatisfactory

Salvage chemotherapy and ASCT

The current standard treatment strategy for patients with DLBCL in R/R after R-CHOP is represented
by platinum chemotherapy and HDC-ASCT.
The effects of ASCT were first evaluated in 1995, when the PARMA study confirmed that 2 cycles of salvage chemotherapy (DHAP–dexamethasone, high-dose cytarabine, and cisplatin) plus HDC (BEAC–carmustine, etoposide, cytarabine, and cyclophosphamide) combined with ASCT improved EFS and OS
compared to 6 cycles of DHAP.

Several subsequent studies have focused on improving transplant outcomes, primarily modifying salvage or pretreatment protocols
.
In phase III CORAL studies, there were no significant differences in response rates (62.
8% vs 63.
5%), EFS (26% vs 35% at 3 years) or OS (47% vs 51% at 3 years) compared with R-DHAP.
The trial also included a secondary randomization of ASCT followed by ascite following pretreatment with BEAM (carmustine, etoposide, cytarabine, and melphalan) and then randomized to rituximab or placebo maintenance therapy, although there was no difference in outcomes
.
Because of this data, rituximab maintenance therapy
after ASCT is not recommended.

Similar results were observed in the NCIC-CTG LY study, with GDP (gemcitabine, dexamethasone, and cisplatin) having similar response rates compared to DHAP (45.
2% vs 44%), and no difference in EFS and OS, but lower
toxicity.
The studies also highlight the most relevant prognostic factors influencing remission rates
in this context.
In CORAL studies, relapse within 12 months of diagnosis, aa-IPI score (saaIPI) >1 at relapse, and previous rituximab therapy were associated with poor prognosis; Retrospective analysis of coral studies also confirmed the prognostic value of COO status: GCB-like DLBCL appeared to have a better response rate to R-DHAP than R-ICE
.
Therefore, the results of the above regimens are similar, and the choice of salvage therapy should take into account comorbidities, clinician experience, and pathological features, with R-DHAP preferred, particularly GBB-like DLBCL
.

Although no pretreatment protocol has proven to be better, BEAM
is usually preferred.
Rituximab may also be included in pretreatment regimens, but no significant benefit
has been shown.

As mentioned earlier, the most important factor influencing post-transplant outcomes is the response to first-line and salvage regimens
.
For example, in the CORAL study, only 46% of patients who relapsed within 12 months after diagnosis responded to salvage therapy, while 88% of patients who relapsed after 12 months responded; This different response rate is also reflected in large differences in EFS (23% and 64%
at 3 years, respectively).
In addition, only half of the patients in the CORAL and NCIC-CTG LY.
12 studies received ASCT, largely due to failure
of salvage regimens.
Similarly, in the PET era, multiple studies have shown that patients who did not reach a PET-negative state before transplantation had a higher
risk of recurrence.

Overall, ASCT still has a major role in the treatment of patients with long-term recurrence and chemotherapy-sensitive R/R DLBCL, however patients who relapse within 12 months of diagnosis require the same new strategies
as patients who did not achieve PET-negative CR at the time of transplantation.

CAR-T therapy

Patients with DLBCL who have failed R-CHOP treatment, are not suitable for transplantation, or who have a very poor prognosis with standard chemotherapy for RELAPS/refractory HDC-ASCT, are effective in
the treatment of B-cell malignancies, including DLBCL.
Anti-CD19 CAR-T therapy includes clearing gonorrhea chemotherapy (usually based on fludarabine plus cyclophosphamide or bendamustine), followed by a single CAR-T infusion
。 There are currently three CAR-T products available for DLBCL treatment: Axicabtagene ciloleucel (Axi-cel), Tisagenlecleucel (Tisa-cel), and Lisocabtagene maraleucel (Liso-cel), which are characterized by similar efficacy, but structural differences are mainly due to different co-stimulatory domains (Axi-cel is CD28, Tisa-cel And Liso-cel is a unique CD4+/CD8+ balance ratio of 4-1BB and Liso-cel
.
In three key studies, ZUMA-1 (Axi-cel), JULIET (Tisa-cel), and TRANSCEND NHL 001 (Liso-cel), all three products showed higher efficacy in DLBCL R/R after previous ≥ 2-line treatment: ORR ranged from 52-83%, CR was 40%-58%, median PFS was 5.
9 months to NR, and DOR was 11-23 months
。 However, the specific toxicity of CAR-T (such as CRS and neurotoxicity) is also of concern, with CRS occurring in 93% of patients (11% ≥ grade 3) in ZUMA-1, 93% of patients in JULIET (21% ≥ grade 3) and 42% of patients in TRANSCEND NHL 001 (2% ≥ 3), compared with 64% of patients in ZUMA-1 (32% ≥ grade 3), 58% of patients in JULIET (12% ≥ grade 3) and TRANSCEND NHL Neurotoxicity occurs in 30% of patients (10% ≥ grade 3) in 001
.
CAR-T is currently considered the gold standard for third-line treatment of R/R DLBCL, and real-world data from the United States and Europe confirm its efficacy
.

CAR-T is treated in the second line

The impressive results of CAR-T in third-line therapy have prompted people to test them as second-line treatments
for refractory DLBCL.
Three large randomized phase III studies have compared three CAR-T products with salvage platinum-based chemotherapy after chemotherapy HDC-ASCT (standard of care, SOC) in patients with refractory DLBCL who do not respond to first-line therapy or recur within 12 months
。 The ZUMA-7 study (Axi-cel vs.
SOC) and the TRANSFORM study (Liso-cel vs.
SOC) randomized 359 and 194 patients, respectively, demonstrated the efficacy of both CAR-T products over SOCs, including treatment response (CR 65% vs.
32% vs.
66% vs.
39%) and survival (median EFS 8.
2 months vs.
39%, respectively).
2 months, 10.
2 months vs.
3.
1 months) [41,42].

However, the BELINDA study did not observe a difference of CR 28.
4 vs.
27.
5% between Tisa-cel and SOC, with a median EFS of 3 months).
)
The differences in results from these studies can be explained in part by differences in study design, including that ZUMA-7 does not allow bridging therapy, which may have selected patients with less aggressive disease, and that CAR-T production in the BELINDA study was longer [23.
5 days in the UNITED States and 28 days in non-U.
S.
countries]
compared to the 13 days of the ZUMA-7 study 。 In addition, interestingly, in 3 studies, patients aged > 75 years were enrolled (the maximum age was 81 years in ZUMA-7, 79 years in BELINDA, and 2 cases in TRANSFORM >75 years).

The positive results of ZUMA-7 established a new therapeutic breakthrough for DLBCL, and Axicel became the first FDA-approved CAR-T product for patients who did not respond to first-line treatment or relapsed within 12 months
.

Mechanism of FAILURE OF CAR-T therapy

More than one-third of patients with R/R DLBCL can be cured with CAR-T therapy, although a significant proportion of these patients will still recur and have poor
outcomes.
Known causes of CAR-T therapy failure are related to patient and disease characteristics, characteristics of CAR-T products, and tumor cell escape mechanisms
.

Pre-infusion factors play a key role in CAR-T efficacy, and the production of cell products requires an adequate absolute lymphocyte count and a long production time (up to 115 days in some cases
).
。 The first preinfusion factor is primarily the number of previous treatments, which can be overcome by gradually moving CAR-T therapy to second-line therapy, as shown in the ZUMA7, BELINDA, and TRANSFORM studies, or eventually moving to first-line therapy, as shown in the ZUMA-12 study design for Axi-cel as part of first-line therapy for high-risk DLBCL patients).

The second preinfusion factor is the limiting factor
of having a highly proliferative disease.
To overcome this weakness, faster protocols for producing CAR-T in the coming years are moving toward the clinic
.

Differences in product characteristics may also affect its anti-tumor activity, and the efficacy of CAR-T therapy is affected
by the phenotypic composition of the cell product.
CAR-T products enriched with central memory T cells have higher cytotoxic activity compared to products with a higher degree of T cell phenotypic
differentiation.

Another mechanism of CAR-T failure is associated
with reduced dysfunction and killing potential.
This factor may be associated with intrinsic dysfunction of engineered T cells or exposure to the immunosuppressive tumor microenvironment; Checkpoint inhibitors and anti-inflammatory molecules in the microenvironment can lead to CAR-T depletion, which is one of the main determinants of clinical outcomes

The final cause of CAR-T failure is related to heterogeneous tumor cell escape mechanisms, the most widely known of which is antigen loss
.
THE SELECTIVE PRESSURE OF CAR-T ON THE TARGET ANTIGEN CAN LEAD TO THE LOSS OF EXPRESSION OF THE ANTIGEN ITSELF, AND MORE THAN 2/3 OF PATIENTS WITH ACUTE LYMPHOBLAS LEUKEMIA UNDERGOING ANTI-CD19 CAR-T THERAPY WITH CD19 NEGATIVE DISEASE RECURRENCE; This phenomenon is less defined in lymphoma until studies such as Neelapu have shown that up to 30 percent of NHL treated with Axi-cel are CD19 negative when they relapse
.
Tumor cell "lineage switch" is another intriguing event that can lead to CAR-T failure, which manifests itself as a phenotypic change in the tumor in different cell lines to avoid the pressure
of choice of CAR-T therapy.
Zhang et al.
described a 2020 report by Blood that mensocytic lymphomas deled into low-differentiated sarcomas
.

Allogeneic stem cell transplantation in the CAR-T era

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the first treatment to establish the role of adoptive cell therapy in curing hematologic malignancies
.
Allo-HSCT harnesses the ability of donor cells to recognize tumor antigens and produce an effective immune response and is considered a potential cure for DLCBL, particularly in patients with previous severe pretreatments
who relapse or progress after ASCT.

EBMT) analyzed 101 patients with DLBCL who received allo-HSCT after previous ASCT from 1997 to 2006 to confirm the important role of allo-HSCT in the challenging pro-treatment patient cohort, with a 3-year non-relapse mortality rate (NRM) of 28.
2%, a 3-year PFS of 41.
7%, and a 3-year OS of 53.
8%.

The analysis also showed that patients with longer PFS than 12 months after ASCT had a longer recurrence; However, this study showed no statistically significant differences between different pretreatment protocols
.
Currently, in the absence of prospective randomized trials, pulp-clearing pretreatment (MAC) or reduced intensity pretreatment (RIC) remains a possible alternative, while MAC appears to be associated with lower recurrence rates but associated with higher NRM incidences; Invasive disease with a high tumor burden and an incomplete response to salvage therapy is likely to be the first choice for MAC
.

Even though allo-HSCT can provide durable disease control in some refractory patients, some concerns about the regimen remain unanswered
.
In fact, infection rates and graft-versus-host disease (GVHD) can affect NRM and quality of life
after allo-HSCT.

In recent years, CAR-T cell therapy has revolutionized the landscape of DLBCL cell therapy options, providing a prominent alternative to cell immunotherapy for patients who have relapsed after ASCT and have previously received too many lines of therapy
.
CAR-T cells also overcome some of the typical problems of allo-HSCT, such as car-T cells that do not need to control disease before infusion, unlike allo-HSCT
.

However, allo-HSCT can still work, especially in patients who have failed car-T cell therapy
.
In addition, if CAR-T cells are not suitable [e.
g.
, patients who cannot undergo monosemothrysis (i.
e.
, patients with cytopenia) or areas where CAR-T cells are not available], allo-HSCT should be recommended

In the future, allo-HSCT can also be used as consolidation therapy after CAR-T cell therapy to improve outcomes, especially in patients with a particularly poor prognosis or not reaching CR, so rigorous collaboration with the cell therapy team is critical
for early identification of patients who may benefit from allo-HSCT.

In addition, allo-HSCT should minimize NRM and toxicity, so that allo-HSCT can be converted to a safer platform and incorporated into other cell therapies (including not only CAR-T cells, but also donor lymphocyte infusions) to achieve better and better disease control
.

Novel salvage therapies beyond CAR-T

In addition to CAR-T, other promising agents are becoming the treatment option for R/R DLBCL (Table 2
).

Tafasitamab + lenalidomide

Tafasitamab is an Fc-enhanced humanized anti-CD19 monoclonal antibody that exhibits activity in B-cell malignancies and has synergistic effects with lenalidomide, which enhances naturally killer cell-mediated, antibody-dependent cytotoxicity (Figure 2
).
The phase II multicenter single-arm L-MIND study ([56] in Table 2) evaluated tafasitamab + lenalidomide (tafa + LEN) combination therapy
in R/R DLBCL not suitable for transplantation.
The course of treatment consists of tafasitamab + lenalidomide for up to 12 months, followed by monotherapy with tafasitamab until disease progression
.
The regimen was highly efficient, with an ORR of 61% (CR 43%), a median duration of remission of 21.
7 months, and a reasonable
toxicity profile.
Based on this result, in 2020, tafasitamab in conjunction with lenalidomide obtained FDA and EMA accelerated approval for the treatment of R/R DLBCL
that is not suitable for transplantation.

An observational retrospective study, RE-MIND2, compared patient outcomes in patient populations
in L-MIND studies with patient populations treated with R/R DLBCL unsuitable for transplantation with treatment of NCCN and ESMO-recommended therapies 。 In a 1:1 matching analysis based on propensity scores, tafa+ LEN showed better OS and ORR relative to polatuzumab vedotin + rituximab and bendamustine (Pola-BR) and rituximab + lenalidomide (R2), and the outcomes were comparable to those against CD19 CAR-T, thus commenting on their high efficacy in the context of R/R DLBCL, but its shortcomings lie in retrospective controls
.

Bispecific antibodies

Bispecific antibodies (BsAbs) are monoclonal antibodies that recognize two specific antigens or epitopes and redirect autologous T cells against tumor cells (Figure 3
).
Several different anti-CD20 BsAbs have been studied in R/R DLBCL recently, and the results show that they have good activity even in multi-refractory patients and are safe and controllable, manifested by a low incidence of CRS and neurotoxic events, mostly grades
1-2.

Mosunetuzumab is a full-length, fully humanized IgG1 BsAb that targets CD3
on T cells and CD20-positive B-NHL cells.
The final results of phase I/Ib studies of dose-escalation for the treatment of R/R inert and invasive BNHL cohorts showed an ORR of 34.
9% (19.
4% CR) in the invasive BNHL subgroup and a duration of remission (DOR) of 16.
8 months for all responders, with 20.
4 months
for CR patients.
The results were promising and tolerable, with no dose-limiting toxicity, with CRS of 27.
3% and only 1% of grade 3 neurotoxic events, and 4.
1% of grade 3 neurotoxic events; An expanded part of the study is still ongoing
.

Glofitamab is another CD3 x CD20 BsAbs characterized by a 2:1 structure consisting
of two fragments targeting the CD20 antigen and a single CD3-bound fragment.
It is administered before a single dose of otolizumab (1000 mg) with the aim of reducing mature circulating B cells and minimizing systemic cytokine release syndrome
。 In phase I trials containing different intensive pretreatment B-NHL subtypes, fairly good efficacy was observed in R/R DLBCL: the median observation period was 27.
4 months, the global ORR was 41.
1% (CR 28.
8%), the orr in the ≥ 10 mg group was 55% (CR 42.
1%), the median DOR was 5.
5 months, and the median DOR was not reached
in patients who achieved CR 。 Glofitamab showed durable remission in 51.
6% (CR 39.
4%) and a median DOR of 12.
6 months (patients received extensive pretreatment, with 52 previous CAR-T treatment failures in 155 patients).

Epcoritamab (GEN3013) is the first subcutaneous CD3 x CD20 BsAb that binds to the EPITOP OF CD20 antigen unlike the most common anti-CD20 monoclonal antibody
。 It is safe to manage, with 59% of CRS events of grade 1-2 and significant activity against R/R B-NHL, including orr of 68% (45% CR) at full dose (12-60 mg) and ORR 88% (38% CR) at final recommended dose (48 mg).

。 The latest data from the Phase II DLBCL extended cohort of the key study (EPCORE NHL 1) confirmed the activity of Epcoritamab in R/R DLBCL: 63% (39% CR) of 157 enrolled patients (61/157 R/R in CAR-T) and a median DOR of 12 months
.

Other CD3 x CD20 BsAbs that R/R NHL is in the middle of the study include odronextamab and Plamotamab, whose early study data are encouraging
。 Plamotamab's study is still preliminary, but odronextamab showed a lasting response to R/R B-NHL in a phase I dose-escalation study, particularly when administered at a dose of >80 mg, the ORR of the DLBCL subgroup that had not previously been treated with CAR-T was 60% (CR 60%), compared with 33.
3% (CR 23.
8%) for patients with CAR-T R/R, with a median DOR It was 10.
3 months and 2.
8 months
, respectively.
Data from the odronextamab Phase I study led to a global Phase II trial of R/R B-NHL, which is currently underway
.

Antibody drug conjugates

There are two ADCs in R/R DLBCL that play a major role
.

Polatuzumab vedotin: Polatuzumab vedotin monotherapy with B-NHLs has a certain efficacy and is well tolerated, and neurotoxicity is the main adverse event
that occurs after treatment 。 In a phase II randomized study conducted by Sehn et al.
, polatuzumab vedotin combined with rituximab and bendamustine (pola-BR) was more effective than standard BR, including remission (CR 40% vs.
17.
5%) and long-term survival (median follow-up of 22.
3 months; median PFS 9.
2 vs.
3.
7 months, HR= 0.
36; median OS 12.
4 vs.
4.
7 months, HR = 0.
42).

。 These results led the FDA and EMA to approve the pola-BR regimen for the treatment of R/R DLBCL
that is not suitable for transplantation.
In a recently published updated analysis, an expanded cohort of 106 patients with R/R DLBCL treated with pola-BR was added, and the protocol confirmed efficacy, reaching CR and sustained survival of 38.
7%, but the PFS rate was reduced: median PFS was 6.
6 months and median OS was 12.
5 months
.
True-data response rates for pola-BR treatment of R/R DLBCL were similar, with ORR ranging from 48% to 60%, but PFS was shorter (3 to 5.
6 months).

。 Driven by positive pola-BR outcomes, several trials are investigating the efficacy of polatuzumab in combination with other chemical immunotherapy regimens (e.
g.
, rituximab + isotifamide, carboplatin, and etoposide (polaR-ICE) as a pre-ASCT salvage therapy for transplant patients, as well as comparing poratuzumab + rituximab to gemitabine + oxaliplatin (pola-R-GemOx) versus R-GemOx treatment not suitable for transplantation Phase III study of R/R DLBCL POLARGO
.

Loncastuximab tesirine：

Loncastuximab tesirine consists of a humanized anti-CD19 monoclonal antibody with pyrrolidindiazepine dimer cytotoxic alkylating agent tesirine (SG3199) that exhibited safe toxicity characteristics in the Phase I study, based on the results of the multicenter Phase II LOTIS-2 trial, which received accelerated FDA approval for the treatment of R/R DLBCL
in 2021 。 In the LOTIS-2 study, 145 patients with severe pretreatment with DLBCL (median 3 previous treatment lines) received intravenous administration of loncastuximab tesirine every 21 days for up to 1 year or until disease progression or unacceptable toxicity
developed.
The ORR was 48.
3% (CR 24.
1%), the 9-month DOR was 64%, and the median PFS and OS were 4.
9 months and 9.
9 months
, respectively.
A phase I multi-arm study that has not yet been recruited will evaluate the activity
of loncastuximab tesirine in combination with several chemotherapy or biologics, including gemcitabine, lenalidomide, polatuzumab vedotin, or the PI3K inhibitor umbralisib, in the treatment of R/R B-NHL 。 To improve its efficacy, the Phase 2 Single-Arm Study of R/R DLBCL and Sock cell lymphoma (LOTIS-3) also combined loncastuximab tesirine with ibutinib; Preliminary results from the first 35 patients recently reported confirmed a 57.
1% improvement in ORR (CR 34.
3%), but more data on longer follow-up times are needed to confirm whether combination therapy is superior to monotherapy
.

Early use of immunotherapy

The positive results of innovative therapies such as tafa + LEN, BsAbs, and CAR-T for R/R DLBCL have prompted attempts to introduce it to first-line treatments
.

In the first-MIND Phase Ib study, newly diagnosed patients with DLBCL were randomized to receive tafa + R-CHOP or tafa + LEN + RCHOP
.
Both combination regimens are acceptable for toxicity, similar
to the expected toxicity of the standard R-CHOP regimen.
This prompted the launch of a phase III multicenter randomized double-blind study (frontMIND) to compare the safety and efficacy of R-CHOP with the triple regimen tafa + LEN + R-CHOP for
the treatment of untreated, high-risk DLBCL, which is ongoing.

In the CD3xCD20 BsAbs field, many drugs are being added to standard R-CHOP
in first-line studies.
In a study containing R/R B-NHLs and newly diagnosed high-risk DLBCL, 27 patients in the untreated subpopulation of DLBCL were assessable, and the CRS of mosunetuzumab combined with CHOP was controllable (grade ≤2) and non-neurotoxic, with an ORR of 96% (CR 85%)
。 Mosunetuzumab as a consolidation therapy for patients with DLBCL whose first-line response to R-CHOP is not satisfactory (SD or PR) after phase I/II, or mostuzumab +/-Polatuzumab vedotin as a first-line treatment in elderly/unfit patients who are not candidates for chemoimmunotherapy is being explored
.
In a preliminary analysis of the latter study, mosunetuzumab monotherapy (group B) yielded good results with an ORR of 58% and a CR of 42%.

Glefitamab plus R-CHOP treatment, including R/R B-NHL and newly diagnosed DBCL
, is currently being evaluated in a Phase Ib study (NCT03467373).
Very preliminary data from the DLBCL cohort safety phase phase show the safety of combination therapy, with only 1 grade 1 CRS event occurring, no neurotoxic events occurring, and 4/4 CR
cases observed in patients with assessable remission 。 In one Phase I/II study, the safety and efficacy of Epcoritamab plus various standard therapies for untreated and R/R B-NHL, including for the combination of Epcoritamab + R-CHOP for initial treatment of high-risk DLBCL and Epcoritamab + Gemox combination therapy for R/R DLBCL
that is not suitable for transplantation or CAR-T failure 。 Preliminary data from a small number (33) of untreated, high-risk DLBCL patients show that the combination of Epcoritamab + R-CHOP has reasonable toxicity and encouraging anti-lymphoma activity, with 52% of CRS ≤ grade 2 (except 1 patient with grade 3) and all assessable patients (31 patients) achieving early remission (ORR 100%, CMR 77%); In 27 patients with R/R DLBCL, Epicortimab + Gemox were initially shown to be safe (CRS 70%, grade 1-2 except for 1 case of grade 3) and good efficacy (ORR 92%, CMR 60%)
.

Based on the good efficacy of anti-CD19 CAR-T in second- or ≥ third-line R/R DLBCL, this cell therapy has been incorporated into the early treatment phase
of high-risk DLBCL.
In the phase II ZUMA-12 study, patients with high-risk DLBCL (defined as IPI≥3 or double/triple hit) who were PET positive in the midterm after 2 courses of anti-CD20-anthracycline regimen were treated
with Axicabtagene ciloleucel 。 Preliminary data from the study showed rapid and long-lasting remission, with ORR 89% (78% CR), 12-month PFS, EFS, DOR, and OS 81%, 73%, 75%, and OS, respectively, and median follow-up of 15.
9 months median PFS, EFS, and DOR not being achieved
.
These results have led to further exploration of the use of CAR-T in first-line therapies for high-risk DLBCL, based on the assumption that patients with fewer previous treatments and stronger immune systems will benefit more
.

Precision medicine and tailor-made

DLBCL is currently considered a phenotypic and genetically heterogeneous disorder
.
Initially defined as DLBCL as ABC, GCB and three different subtypes that cannot be classified according to the COO, it was subsequently recognized
in the 2016 REVISED CLASSIFICATION OF LYMPHOPATHS BY THE WORLD.
Two recent independent studies based on total exon sequencing and structural genomic anomalies have defined two "molecular classifications" that classify DLBCL into subtypes characterized by targetable genetic alterations, paving the way
for a new era of precision medicine.
In a recent study by Wilson et al.
, extended genomic analysis of non-GCB DLBCL patients studied by PHOENIX was designed to identify molecular subgroups
with different sensitivities to ibutinib + R-CHOP combination therapy.
The authors grouped patients according to the classification of Schmitz et al.
, and identified patients with MDC, BN2, and N1 molecular subtypes
.
Younger subjects (aged ≤60 years) with MDC or N1 with MUTATIONs in MYD88, CD79b, or NOTCH1 were more sensitive to ibutinib and had significantly improved outcomes after the addition of ibutinib compared with the standard group, with 3-year EFS of 100%, 42.
9%, and 50%,
respectively, for both subtypes 。 The preliminary results of the Guidance-01 Phase II study were presented at the 2021 International Conference on Malignant Lymphoma, in which 128 newly diagnosed DLBCL cases were divided into 6 subgroups using simplified targeted sequencing tools, including 4 subtypes previously described by Schmitz et al.
(MCD-like, BN2-like, N1-like, EZB-like), TP53 mutations, and others
。 Patients were then randomized on a 1:1 basis with standard R-CHOP or R-CHOP+X, with drugs added according to molecular subgroup regulation: ibutinib to MCD and BN2, demethylated decitabine to TP53 mutation, tucidinostat (histone deacetylase inhibitor) to EZB, lenalidomide to N1, and others
。 Among the 107 patients assessable at the time of analysis, the response rate was higher in the R-CHOP +X group (CR: 87% versus 66% versus the standard cohort, respectively), and ultimately led to an improvement in PFS (96% and 79% of 1-year PFS, HR = 0.
22).

Despite the small sample size, this "proof-of-concept" study may suggest potential benefits for tailored, mechanism-based treatment strategies and encourage further research
in this direction.

conclusion

Since the introduction of R-CHOP, there have been many academics working to improve the outcome of DLBCL, especially since the past decade has changed a lot, with new treatments in R/R patients improving life expectancy
.
The advent of CAR-T opened the door to a new era for patients who do not respond to chemotherapoimmunotherapy, which is now the standard 3-line treatment for R/R DLBCL, and data from new studies also allows them to be used as second-line treatment
in patients with refractory or early relapse.
For patients with R/R who are not candidates for transplantation, combined pola-BR is a new option to improve outcomes
in patients who have not previously had an effective alternative treatment.
Recent novel drugs have shown impressive results in treating unresponsive patients, including the combined TAFA+ LEN regimen approved by the FDA and EMA for R/R patients and CD3 x CD20 BsAbs, which has shown efficacy even in patients with severe pre-treatment
.

On the other hand, however, although many studies aim to improve first-line treatment outcomes, standard treatment after 20 years is still represented
by R-CHOP.
While R-CHOP+X has many different combinations, it is not easy
to explain why this strategy fails.
Targeting individual genetic alterations based on overly simple subgroups (GCBs or ABC) may not be effective enough, causing lymphoma cells to escape
through other pathways.
In fact, DLBCL is more complex and heterogeneous, and as the latest molecular classifications and novel combinations of adding multiple new drugs to standard R chemotherapy suggest, perhaps strategies based on a particular mutation may have a better
chance of success.
Recently, however, something has begun to change, with R-CHOP plus X (i.
e.
, pola-R-CHP) showing for the first time better than R-CHOP in the POLARIX study, and the Phase II CAVALLI trial with Venequera on top of R-CHOP appears to improve outcomes
in the poorly prognostic subgroup of BCL-2 overexpression 。 In addition, ongoing studies are examining the efficacy of early use of immunotherapy (first-MIND study, tafa + LEN) plus R-CHOP first-line treatment of R/R patients, including several studies that add CD3 x CD20 BsAbs, such as mosunetuzumab, epcoritamab and glofitamab
.

A real breakthrough in the first-line treatment of DLBCL in the future may manifest itself in the adoption of individualized strategies
tailored to clinical and molecular characteristics.
Molecular analysis of the PHOENIX study by Wilson et al.
revealed this finding, and more deeply, the preliminary results of the Guidance-01 study suggest a shift
in that direction.
Further exploration of molecularly based therapeutic strategies should be encouraged, and translating advanced sequencing techniques into simplified platforms capable of capturing relevant tags from different genetic subgroups may be the next step
in increasing the viability of this strategy.

Given the current dynamic landscape of new biologics and innovative combinations, the authors summarize possible strategies for treating DLBCL in 2022 in Figure 4, but as a famous song put it, "The times they are a-changing," this strategy may need to be updated
in the near future as ongoing research publishes results.

References

Stefano Poletto,et al.
Treatment strategies for patients with diffuse large B-cell lymphoma.
Cancer Treat Rev .
2022 Jul 31; 110:102443.
doi: 10.
1016/j.
ctrv.
2022.
102443.